DESCRIPTION: (Verbatim from the Applicant's Abstract) Peroxisomal biogenesis disorders represent a group of disorders that derive from defects in the biogenesis of peroxisomes including defects in the Peroxisomal protein import machinery. We have reported a Peroxisomal disease with an abnormality of catalase import into peroxisomes which manifests as a neurological disease with clinical and biochemical features similar to infantile Refsum-Zellweger type disease due to the inactivation of peroxisomal functions as a result of alteration in peroxisomal/cellular redox (Hydrogen Peroxide). The objective of this proposal is to decipher the peroxisomal catalase import machinery and to elucidate the molecular defect in cell lines from patients with abnormal targeting of catalase, and antioxidant enzyme that detoxifies H2O2 to H20, in peroxisomes. Excessive H2O2 in these catalase-negative peroxisomes results in alterations in peroxisomal/cellular redox and subsequent inactivation of peroxisomal enzyme activities. Achievement of these goals will be facilitated by cloning and sequencing of cDNA for protein (s) that are required for targeting of catalase to peroxisomes. The antibodies and cDNA generated under specific aim I will be utilized to decipher the molecular basis of the abnormality by identification of the protein component (s) of the catalase import machinery tat is defective in cell lines from patients with catalase-negative peroxisomes. The possible role of peroxisomal/cellular redox (e.g., O2 and H2O20 in the modulation of peroxisomal functions (alpha-oxidation of phytanic acid) in the metabolic biology of this disease process will be investigated under specific aim III. The proposed studies will utilize state-of-the-art techniques in genetics, cellular biology and biochemistry and will provide a better understanding of the molecular basis of the defect in intracellular targeting of catalase.